This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The extracellular signal regulated kinase ERK2 is an important mediator of cell proliferation and has been implicated in a number of cancers. Inhibiting its kinase activity directly is problematic due to similarities of ATP-binding regions of different kinases and importance of ERK2 in normal cell functioning. The goal of this project is to develop specific ERK2 activity inhibitors which disrupt its interaction with protein substrates (e.g. c-Myc, c-Fos, RSK-1, and ELK-1) and thus act in specific and ATP-independent manner. Crystal structures of protein-inhibitor complexes will be used to understand the mechanisms by which small ligands interfere with cell signaling and will lead to rational design of improved inhibitors using the information about specific interactions. We have successfully co-crystallized ERK2 with several inhibitors identified by combination of structure-based drug design and functional assays. Crystals are small and use of synchrotron radiation allows to obtain data at 2[unreadable] resolution and higher. This greatly enhances the level of detail at which the protein-ligand interactions are revealed. Due to the nature of the project, large numbers of crystals have to be screened, further necessitating the access to synchrotron radiation source.